Cognitive impairments, including memory loss, are prevalent in the elderly and patients with neurodegenerative disease. However, the exact causes of aging-related cognitive impairments are uncertain, and effective prevention and treatment options are limited. Increasing evidence implicates astrocytic-neuronal interactions in a wide range of normal and pathophysiological processes, including memory loss and neurodegeneration. However, the exact mechanisms by which astrocytes may contribute to disease-related cognitive impairments are not known. Transactive response DNA-binding protein 43 kDa (TDP-43) is associated with diverse aging- related neurodegenerative disorders and its dysfunction correlates with cognitive decline in humans. Recent studies suggest that glial TDP-43 plays important roles in the brain and its dysfunction might contribute to disease pathogenesis. In support, mutant TDP-43 can cause cell-autonomous impairments in isolated astrocytes and its astrocytic expression in animal models causes behavioral deficits and premature mortality, suggesting that astrocytic TDP-43 is essential for brain function and its dysregulation can cause disease. Despite these intriguing findings, the roles of astrocytic TDP-43 in cognitive decline and astrocytic-neuronal interactions are not known. Our preliminary studies suggest that astrocytic TDP-43 dysregulation occurs in human cases with Alzheimer?s disease and causes memory loss in transgenic mouse models. In addition, our results implicate astrocytic TDP- 43 in regulating glial and neuronal gene expression, astrocytic-neuronal interactions, and neuronal plasticity. However, these effects and causal links between astrocytic TDP-43 dysregulation and neuronal activities linked to memory require further investigation. Here, we will investigate how astrocytic TDP-43 dysfunction affects the brain in common dementias by defining its roles in hippocampus-dependent memory (Aim 1), gene expression, neuronal activities (Aim 2), and astrocytic-neuronal signaling mechanisms (Aim 3). In these studies, we will test novel hypotheses that astrocytic TDP-43 dysregulation alters astrocytic-neuronal chemokine signaling and specific aspects of glutamatergic transmission and neural plasticity. We will use a combination of advanced molecular and cellular approaches in transgenic mice and cell cultures to target and probe specific cell populations and brain regions. These studies are poised to reveal novel TDP-43-linked mechanistic cascades, advance our understanding of how astrocytic-neuronal interactions contribute to cognitive decline, and identify novel therapeutic strategies that reduce TDP-43-linked deficits in diverse disorders.